A RET inhibitor offered substantial benefits in patients with thyroid cancer and those with non-small-cell lung cancer (NSCLC), according two early-phase trials, which led the FDA to fast-track approval for the agent.
In the phase I/II LIBRETTO-001 trial, selpercatinib (Retevmo) treatment resulted in durable efficacy, with primarily low-grade toxic effects, in patients with medullary thyroid cancer, with and without previous treatment with a multi-kinase inhibitor (MKI) or a tyrosine kinase inhibitor (TKI), reported Lori J. Wirth, MD, of Massachusetts General Hospital (MGH) in Boston, and co-authors reported in The New England Journal of Medicine.
Additionally, the the authors reported that the agent had benefits in previously treated, RET fusion–positive thyroid cancers of various histologic types.
“For patients living with these cancers, the approval of selpercatinib means they now have a treatment option that selectively and potently inhibits RET,” Wirth said in an Eli Lilly press release. “Based on the published data for this new medicine, as well as my personal experience treating patients, this may be a good treatment option.”
Also as part of the phase I/II LIBRETTO-001 trial, and also reported in NEJM, selpercatinib demonstrated durable efficacy, including intracranial activity, and again with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC, according to Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York City, and co-authors.
The results held true in patients who had previously received platinum-based chemotherapy and in treatment-naïve patients, they reported in NEJM.
“RET fusions are found in up to 2% of NSCLCs, but when you look at the global incidence of lung cancer, the absolute number of [RET-fusion positive NSCLC] cases are actually substantial…there’s definitely an unmet need,” Drilon told OncLive TV at the 2019 World Conference on Lung Cancer. “I think this is a win for patients.”
Selpercatinib received FDA orphan drug status in 2019, a green light for priority review in January 2020, and approval in May 2020 as therapy for the following:
- Adults with RET fusion-positive NSCLC.
- Adult and pediatric patients (ages ≥12 years) with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, or advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory.
In an accompanying NEJM editorial, Razelle Kurzrock, MD, of the Moores Cancer Center at the University of California San Diego, noted that “among diverse cancers, RET aberrations have been identified in approximately 2% of cases, with mutations being the most common alteration. Mutations constitute approximately 37% of RET alterations, followed by fusions (approximately 31%) and amplifications (approximately 25%).”
Given the ties between RET germline mutations and/or fusions to various types of thyroid and lung cancers, “RET is thus an attractive therapeutic target…Taken together, these results [of the two studies] show that selpercatinib had marked and durable antitumor activity in most patients with RET-altered thyroid cancer or NSCLC,” she stated.
Kurzrock said that future research should look at ways to introduce selpercatinib, and other RET inhibitors, earlier in the course of the disease, address genomic co-alterations with customized combination therapy, and molecular profiling, such as those discussed in 2019 studies by Kurzrock and co-authors.
Wirth’s group enrolled patients (mostly in their mid-50s; majority were white) with RET-mutant medullary thyroid cancer and those with RET fusion-positive thyroid cancer. Some of the patients with RET-mutant disease had previously received the MKI vandetanib (Caprelsa) or the TKI cabozantinib (Cabometyx).
The study’s primary endpoint was a complete or partial objective response rate (ORR) as determined by an independent review committee, while secondary endpoints included progression-free survival (PFS) and safety.
Wirth and co-authors reported that in the first 55 consecutively enrolled patients, the ORR was 69%
(95% CI 55 to 81). The 1-year PFS was 82% (95% CI 69 to 90). Also, in the 88 previously untreated patients with RET-mutant medullary thyroid cancer, the ORR was 73% (95% CI 62 to 82) and the 1-year PFS was 92% (95% CI 82 to 97).
And in 19 patients with previously treated RET fusion–positive thyroid cancer, the ORR was 79% (95% CI 54 to 94), and the 1-year PFS was 64% (95% CI 37 to 82).
The most common adverse events (AEs) ≥3 were hypertension (21% of patients), increased alanine aminotransferase (ALT) level (11%), increased aspartate aminotransferase level (9%), hyponatremia (8%), and diarrhea (6%).
The authors noted that among all 531 treated patients, only 2% discontinued selpercatinib because of drug-related AEs, most commonly elevated ALT levels and drug hypersensitivity.
“What we’re seeing is a combination of very good efficacy and also very good tolerability with selpercatinib,” Wirth said in an MGH press release. “The response rates are high, responses are very durable, and overall the drug does not cause a lot of toxicity.”
Drilon and co-authors enrolled patients (median age 61 years; majority female) with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy, and previously untreated patients separately. The study’s primary and secondary endpoints were the same as those looked at by Wirth and co-authors.
They found that among the first 105 consecutively enrolled patients with RET fusion-positive NSCLC, who had undergone chemotherapy, the ORR was 64% (95% CI 54 to 73) while the median duration of response was 17.5 months (95% CI 12.0 to could not be evaluated). Of those patients, 63% had responses that were ongoing at a median follow-up of 12.1 months.
Among 39 treatment-naïve patients, the ORR was 85% (95% CI 70 to 94), and 90% of the responses were ongoing at 6 months. In 11 patients with measurable central nervous system metastasis at enrollment, the objective intracranial response was 91% (95% CI 59 to 100).
At 1 year, 66% (95% CI 55 to 74) of all patients were progression-free, and the median PFS was 6.5 months (95% CI, 13.7 to NE).
Drilon’s group noted that the most common AEs (grades ≥3) were hypertension (14%), increased ALT level (12%), increased aspartate aminotransferase level (10%), hyponatremia (6%), and lymphopenia (6%). While there were half a dozen grade 5 AEs (4%), such as sepsis, cardiac arrest, pneumonia, and respiratory failure, the events were not related to selpercatinib treatment, they added.
Once again, 2% of patients stopped selpercatinib because of a drug-related AEs of ALT levels and drug hypersensitivity.
Drilon and co-authors pointed out that “The activity of selpercatinib in our trial was broadly similar to that of targeted therapy in patients with NSCLC that harbors other established oncogenic drivers…for which [TKIs] have been established as first-line therapy,” with the added bonus of “promising frequency of intracranial response to selpercatinib.”
Two confirmatory phase III trials (LIBRETTO-43 and LIBRETTO-531) are currently enrolling patients, according to Eli Lilly, which acquired the agent’s developer, Loxo Oncology, in 2019.
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RET inhibitor selpercatinib (Retevmo) showed durable efficacy in patients with medullary thyroid cancer with and without previous treatment with kinase inhibitors.
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Selpercatinib had durable efficacy in patients with RET fusion-positive non-small-cell lung cancer who had previously received platinum-based chemotherapy and in treatment-naïve patients.
Shalmali Pal, Contributing Writer, BreakingMED™
The LIBRETTO-001 trials were funded by Loxo Oncology and grants from the National Institutes of Health and the University of Texas M.D. Anderson Cancer Center.
Drilon disclosed consultant agreements with 14ner Oncology, AbbVie, AstraZeneca, Bayer, Belgene, BergenBio, Blueprint Medicines, Boehringer Ingelheim, Eli Lilly and Company, Exelis, Genentech, GlaxoSmithKline, Helsinn, Henggrui, Ingnyta, Loxo, Merck, Merus, MORE Helath, Pfizer, Pharmakkar, Puma, Roche Health Solutions Inc., Taiho Pharmaceutical, Takeda/Ariad/Millenium, Texa Pharmaceuticals USA, Inc., TP Therapeutics, Tyra Biosciences, and Verastem.
Kurzrock reported personal fees from BioCom/Sysmex, personal fees from Chugai , other from CureMatch, other from CureMetrix, personal fees from EUSA Pharma , other from IDbyDNA, personal fees from LEK Consulting, grants and personal fees from Merck, personal fees from NeoGenomics, personal fees from NeoMed, grants and personal fees from Pfizer, personal fees from Roche, personal fees from Sysmex, grants from Genentech, grants from Serono, grants from Boehringer Ingelheim, grants from TopAlliance, grants from Takeda, grants from Incyte, grants from Debiopharm, grants from Medimmune, grants from Sequenom, grants from Foundation Medicine, grants from Konica Minolta, grants from Grifols, grants from Omniseq, grants from Guardant, outside the submitted work.
Wirth reported receiving advisory board fees from Ayala Pharmaceuticals, Blueprint Medicines, Cue Biopharma, Cullinan Oncology, Genentech USA, Loxo Oncology, Merck, NewLink Genetics, Novartis, and Rakuten Medical, consulting fees and advisory board fees from Bayer HealthCare Pharmaceuticals and Eisai, advisory board fees and fees for serving on a steering committee from Eli Lilly, and fees for serving on a data and safety monitoring board from Iovance Biotherapeutics.
Cat ID: 120
Topic ID: 78,120,730,120,24,935,192,195,65
